New Insights Into the Treatment of Hyperlipidemia: Pharmacological Updates and Emerging Treatments.

Cardiovascular diseases are the leading causes of global mortality and morbidity. Hyperlipidemia is a significant risk factor for atherosclerosis and subsequent cardiovascular diseases. Hyperlipidemia is characterized by imbalances in blood cholesterol levels, particularly elevated low-density lipoprotein cholesterol and triglycerides, and is influenced by genetic and environmental factors. Current management consists of lifestyle modifications and pharmacological interventions most commonly consisting of statins. This review paper explores pathophysiology, management strategies, and pharmacotherapies including commonly used well-established medications including statins, fibrates, and ezetimibe, exciting novel therapies including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and RNA interference therapies (inclisiran), lomitapide, and bempedoic acid, highlighting their mechanisms of action, clinical efficacy, and safety profiles. Additionally, emerging therapies under clinical trials including ApoC-III inhibitors, DGAT2 inhibitors, ACAT2 Inhibitors, and LPL gene therapies are examined for their potential to improve lipid homeostasis and cardiovascular outcomes. The evolving landscape of hyperlipidemia management underscores the importance of continued research into both established therapies and promising new candidates, offering hope for more effective treatment strategies in the future.

De Winter's ECG: Not your usual STEMI.

We report a 39-year-old male who presented with severe chest pain and diaphoresis who suffered from pulseless polymorphic ventricular tachycardia en route to the hospital. His initial electrocardiogram showed De Winter's Pattern (dWP). Coronary angiography revealed 100% thrombotic ostial occlusion of the left anterior descending artery. In young males presenting with chest pain and diaphoresis, dWP should be part of a clinician's differential diagnosis when analyzing the initial electrocardiogram. The medical community needs increased awareness to prevent delay of revascularization because dWP is an ST-segment elevation myocardial infarction (STEMI) equivalent and does not present like a typical STEMI on electrocardiogram.

A low-dose thrombolytic infusion protocol for safe and successful treatment of left ventricular assist device thrombosis: a case series.

Background: Pump thrombosis is a serious complication of continuous-flow left ventricular assist device (CF-LVAD) therapy. In this study, we aim to report a novel protocol of an intermittent, low-dose, and slow infusion of tissue plasminogen activator (alteplase). Case summary: We treated seven LVAD pump thrombosis events (HeartMate® II and HeartWare) in four patients with a median age of 52 years (31-63), and all were female. The protocol was applied from January 2015 to December 2018, and it consisted of an intermittent, low-dose, and slow infusion of systemic thrombolytic therapy in the intensive care unit. This therapy resulted in successful resolution of pump thrombosis in six out of seven events. Bleeding complication occurred in one patient, which included a ruptured haemorrhagic ovarian cyst and a small cerebellar intra-parenchymal haemorrhage. All patients were discharged home in a stable condition, except one patient who died during hospitalization because of severe sepsis, pump thrombosis with subsequent pump exchange, and multi-organ failure. Discussion: A low-dose, prolonged, and systemic thrombolytic infusion protocol is an effective and relatively safe treatment that can lead to a sustained resolution of pump thrombosis with low bleeding complications and failure rates.

Cleavage and Polyadenylation-Specific Factor 4 (CPSF4) Expression Is Associated with Enhanced Prostate Cancer Cell Migration and Cell Cycle Dysregulation, In Vitro.

Potential oncogene cleavage and polyadenylation specific factor 4 (CPSF4) has been linked to several cancer types. However, little research has been conducted on its function in prostate cancer (PCa). In benign, incidental, advanced, and castrate resistant PCa (CRPCa) patient samples, protein expression of CPSF4 was examined on tissue microarray (TMAs) of 353 PCa patients using immunohistochemistry. Using the 'The Cancer Genome Atlas' Prostate Adenocarcinoma (TCGA PRAD) database, significant correlations were found between high CPSF4 expression and high-risk genomic abnormalities such as ERG-fusion, ETV1-fusion, and SPOP mutations. Gene Set Enrichment Analysis (GSEA) of CPSF4 revealed evidence for the increase in biological processes such as cellular proliferation and metastasis. We further examined the function of CPSF4 in vitro and confirmed CPSF4 clinical outcomes and its underlying mechanism. Our findings showed a substantial correlation between Gleason groups and CPSF4 protein expression. In vitro, CPSF4 knockdown reduced cell invasion and migration while also causing G1 and G2 arrest in PC3 cell lines. Our findings demonstrate that CPSF4 may be used as a possible biomarker in PCa and support its oncogenic function in cellular proliferation and metastasis.

Serrate RNA Effector Molecule (SRRT) Is Associated with Prostate Cancer Progression and Is a Predictor of Poor Prognosis in Lethal Prostate Cancer.

Arsenite-resistance protein 2, also known as serrate RNA effector molecule (ARS2/SRRT), is known to be involved in cellular proliferation and tumorigenicity. However, its role in prostate cancer (PCa) has not yet been established. We investigated the potential role of SRRT in 496 prostate samples including benign, incidental, advanced, and castrate-resistant patients treated by androgen deprivation therapy (ADT). We also explored the association of SRRT with common genetic aberrations in lethal PCa using immunohistochemistry (IHC) and performed a detailed analysis of SRRT expression using The Cancer Genome Atlas (TCGA PRAD) by utilizing RNA-seq, clinical information (pathological T category and pathological Gleason score). Our findings indicated that high SRRT expression was significantly associated with poor overall survival (OS) and cause-specific survival (CSS). SRRT expression was also significantly associated with common genomic aberrations in lethal PCa such as PTEN loss, ERG gain, mutant TP53, or ATM. Furthermore, TCGA PRAD data revealed that high SRRT mRNA expression was significantly associated with higher Gleason scores, PSA levels, and T pathological categories. Gene set enrichment analysis (GSEA) of RNAseq data from the TCGA PRAD cohort indicated that SRRT may play a potential role in regulating the expression of genes involved in prostate cancer aggressiveness. Conclusion: The current data identify the SRRT's potential role as a prognostic for lethal PCa, and further research is required to investigate its potential as a therapeutic target.

A Case Report of Brucellosis-Associated Infective Endocarditis.

Brucellosis is a prevalent zoonotic infection that can be relatively well managed and tolerated if appropriate treatment is initiated. Unfortunately, likely secondary to decreased awareness and vague symptoms, the diagnosis can be easily missed leading to worsening complications that severely increase the mortality rate. We present a case of a 25-year-old female who presented from a rural setting with a diagnosis of brucellosis, which was delayed. She ultimately developed infective endocarditis with cardiac vegetations on imaging. Despite improvement on antibiotics and reduction in size of cardiac vegetation, she suffered a fatal cardiac arrest before undergoing surgical intervention. Better awareness regarding hygiene and sanitary food handling should be encouraged, especially in underdeveloped rural areas, to help prevent infection. More studies need to be performed to help better identify symptoms coupled with maintaining a high index of suspicion so as to expedite diagnosis, treatment, management and hopefully prevent the progression of disease and worsening complications.

Surgical Infection Society-Chest Wall Injury Society Recommendations for Management of Surgical Site or Implant-Related Infections After Surgical Stabilization of Traumatic Rib or Sternal Fractures.

Background: Surgical stabilization of rib fractures (SSRF) and surgical stabilization of sternal fractures (SSSF) involves open reduction and internal fixation of fractures with an implantable titanium plate to restore and maintain anatomic alignment. The presence of this foreign, non-absorbable material presents an opportunity for infection. Although surgical site infection (SSI) and implant infection rates after SSRF and SSSF are low, they present a challenging clinical entity. Methods: The Surgical Infection Society's Therapeutics and Guidelines Committee and Chest Wall Injury Society's Publication Committee convened to develop recommendations for management of SSIs or implant-related infections after SSRF or SSSF. PubMed, Embase, Web of Science and the Cochrane database were searched for pertinent studies. Using a process of iterative consensus, all committee members voted to accept or reject each recommendation. Results: For patients undergoing SSRF or SSSF who develop an SSI or an implant-related infection, there is insufficient evidence to suggest a single optimal management strategy. For patients with an SSI, systemic antibiotic therapy, local wound debridement, and vacuum-assisted closure have been used in isolation or combination. For patients with an implant-related infection, initial implant removal with or without systemic antibiotic therapy, systemic antibiotic therapy with local wound drainage, and systemic antibiotic therapy with local antibiotic therapy have been documented. For patients who do not undergo initial implant removal, 68% ultimately require implant removal to achieve source control. Conclusions: Insufficient evidence precludes the ability to recommend guidelines for the treatment of SSI or implant-related infection following SSRF or SSSF. Further studies should be performed to identify the optimal management strategy in this population.

Brain Abscess as a Complication of Hereditary Hemorrhagic Telangiectasia: A Case Report.

An 18-year-old male, previously diagnosed with hereditary hemorrhagic telangiectasia (HHT), presented to the outpatient department with a complaint of generalized seizures and fever for the past five days. He had a history of recurrent epistaxis, progressive shortness of breath, and cyanosis. Magnetic resonance imaging (MRI) of the brain revealed an abscess in the temporoparietal region. A computed angiogram of the pulmonary vasculature showed the presence of arteriovenous malformation (AVM). A four-weekly antibiotic regimen was initiated, which resulted in a profound improvement in symptoms. A brain abscess can arise as a complication of vascular malformation in a patient with HHT, providing a nidus for bacteria to migrate toward the brain. Early recognition of HHT is essential in these patients and their affected family members, as screening can help us prevent complications at an earlier stage.

A randomized clinical trial of glenohumeral joint steroid injection versus suprascapular nerve block in patients with frozen shoulder: a protocol for the Therapeutic Injections For Frozen Shoulder (TIFFS) study.

Frozen shoulder is a common, painful condition that results in impairment of function. Corticosteroid injections are commonly used for frozen shoulder and can be given as glenohumeral joint (GHJ) injection or suprascapular nerve block (SSNB). Both injection types have been shown to significantly improve shoulder pain and range of motion. It is not currently known which is superior in terms of relieving patients' symptoms. This is the protocol for a randomized clinical trial to investigate the clinical effectiveness of corticosteroid injection given as either a GHJ injection or SSNB. The Therapeutic Injections For Frozen Shoulder (TIFFS) study is a single centre, parallel, two-arm, randomized clinical trial. Participants will be allocated on a 1:1 basis to either a GHJ corticosteroid injection or SSNB. Participants in both trial arms will then receive physiotherapy as normal for frozen shoulder. The primary analysis will compare the Oxford Shoulder Score (OSS) at three months after injection. Secondary outcomes include OSS at six and 12 months, range of shoulder movement at three months, and Numeric Pain Rating Scale, abbreviated Disabilities of Arm, Shoulder and Hand score, and EuroQol five-level five-dimension health index at three months, six months, and one year after injection. A minimum of 40 patients will be recruited to obtain 80% power to detect a minimally important difference of ten points on the OSS between the groups at three months after injection. The study is registered under ClinicalTrials.gov with the identifier NCT04965376. The results of this trial will demonstrate if there is a difference in shoulder pain and function after GHJ injection or SSNB in patients with frozen shoulder. This will help provide effective treatment to patients with frozen shoulder.

Downregulation of BUD31 Promotes Prostate Cancer Cell Proliferation and Migration via Activation of p-AKT and Vimentin In Vitro.

Among men, prostate cancer (PCa) is the second most frequently diagnosed cancer subtype and has demonstrated a high degree of prevalence globally. BUD31, also known as Functional Spliceosome-Associated Protein 17, is a protein that works at the level of the spliceosome; it is functionally implicated in pre-mRNA splicing as well as processing, while also acting as a transcriptional regulator of androgen receptor (AR) target genes. Clinically, the expression of BUD31 and its functions in the development and progression of PCa is yet to be elucidated. The BUD31 expression was assessed using IHC in a tissue microarray (TMA) constructed from a cohort of 284 patient samples. In addition, we analyzed the prostate adenocarcinoma (TCGAPRAD-) database. Finally, we used PCa cell lines to knockdown BUD31 to study the underlying mechanisms in vitro.Assesment of BUD31 protein expression revealed lower expression in incidental and advanced PCa, and significantly lower expression was observed in patients diagnosed with castrate-resistant prostate cancer. Additionally, bioinformatic analysis and GSEA revealed that BUD31 increased processes related to cancer cell migration and proliferation. In vitro results made evident that BUD31 knockdown in PC3 cells led to an increase in the G2 cell population, indicating a more active and proliferative state. Additionally, an investigation of metastatic processes revealed that knockdown of BUD31 significantly enhanced the ability of PC3 cells to migrate and invade. Our in vitro results showed BUD31 knockdown promotes cell proliferation and migration of prostate cancer cells via activation of p-AKT and vimentin. These results support the clinical data, where low expression of BUD31 was correlated to more advanced stages of PCa.

Glycyl-tRNA Synthetase (GARS) Expression Is Associated with Prostate Cancer Progression and Its Inhibition Decreases Migration, and Invasion In Vitro.

Glycyl-tRNA synthetase (GARS) is a potential oncogene associated with poor overall survival in various cancers. However, its role in prostate cancer (PCa) has not been investigated. Protein expression of GARS was investigated in benign, incidental, advanced, and castrate-resistant PCa (CRPC) patient samples. We also investigated the role of GARS in vitro and validated GARS clinical outcomes and its underlying mechanism, utilizing The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA PRAD) database. Our data revealed a significant association between GARS protein expression and Gleason groups. Knockdown of GARS in PC3 cell lines attenuated cell migration and invasion and resulted in early apoptosis signs and cellular arrest in S phase. Bioinformatically, higher GARS expression was observed in TCGA PRAD cohort, and there was significant association with higher Gleason groups, pathological stage, and lymph nodes metastasis. High GARS expression was also significantly correlated with high-risk genomic aberrations such as PTEN, TP53, FXA1, IDH1, SPOP mutations, and ERG, ETV1, and ETV4 gene fusions. Gene Set Enrichment Analysis (GSEA) of GARS through the TCGA PRAD database provided evidence for upregulation of biological processes such as cellular proliferation. Our findings support the oncogenic role of GARS involved in cellular proliferation and poor clinical outcome and provide further evidence for its use as a potential biomarker in PCa.

Moebius Syndrome: What We Know So Far.

Moebius syndrome (MBS) is a rare congenital cranial nerve disorder characterized by unilateral, bilateral symmetrical, or asymmetrical facial (VII) and abducens (VI) nerve palsies. Genetics and rhombencephalon vascular disturbances from intrauterine environmental exposures have been attributed to its development. It can present with various orofacial abnormalities. Although the diagnosis is purely clinical, certain characteristic features are present in the brain's images. With no cure, it is essential to devise management on a personalized basis. We discuss etiology, presentation, diagnostic approaches, and effective management in the existing literature. This comprehensive review examines the clinic-pathological aspects of Moebius syndrome. The authors employed the PUBMED base index to identify pertinent literature and reference it according to research keywords. Findings suggest the most popular etiology is the theory of intrauterine vascular disruption to the brainstem during embryogenesis, followed by the genetic hypothesis. Intrauterine environmental exposures have been implicated as potential risk factors. Facial and abducens nerve palsies are the most common presenting features. However, clinical manifestations of lower cranial nerves (IX, X, XI, XII) may be present with orthopedic anomalies and intellectual deficiencies. The diagnosis is clinical with minimal defined diagnostic criteria. Characteristic radiological manifestations involving the brainstem and cerebellum can be observed in imaging studies. With no definitive treatment options, a multidisciplinary approach is employed to provide supportive care. Despite radiological manifestations, Moebius syndrome is diagnosed clinically. Although incurable, a multidisciplinary approach, with personalized rehabilitative measures, can manage physical and psychological deficits; however, standard guidelines need to be established.

Expansion of human amniotic epithelial cells using condition cell reprogramming technology.

Human amniotic epithelial cells (hAECs) are non-immunogenic epithelial cells that can develop into cells of all three germline lineages. However, a refined clinically reliable method is required to optimize the preparation and banking procedures of hAECs for their successful translation into clinical studies. With the goal of establishing standardized clinically applicable hAECs cultured cells, we described the use of a powerful epithelial cell culture technique, termed Conditionally Reprogrammed Cells (CRC) for ex vivo expansion of hAECs. The well-established CRC culture method uses a Rho kinase inhibitor (Y-27632) and J2 mouse fibroblast feeder cells to drive the indefinite proliferation of all known epithelial cell types. In this study, we used an optimized CRC protocol to successfully culture hAECs in a CRC medium supplemented with xenogen-free human serum. We established that hAECs thrive under the CRC conditions for over 5 passages while still expressing pluripotent stem markers (OCT-4, SOX-2 and NANOG) and non-immunogenic markers (CD80, CD86 and HLA-G) suggesting that even late-passage hAECs retain their privileged phenotype. The hAECs-CRC cells were infected with a puromycin-selectable lentivirus expressing luciferase and GFP (green fluorescent protein) and stably selected with puromycin. The hAECs expressing GFP were injected subcutaneously into the flanks of Athymic and C57BL6 mice to check the tolerability and stability of cells against the immune system. Chemiluminescence imaging confirmed the presence and viability of cells at days 2, 5, and 42 without acute inflammation or any tumor formation. Collectively, these data indicate that the CRC approach offers a novel solution to expanding hAECs in humanized conditions for future clinical uses, while retaining their primary phenotype.

The Association between Cyclin Dependent Kinase 2 Associated Protein 1 (CDK2AP1) and Molecular Subtypes of Lethal Prostate Cancer.

Prostate cancer (PCa) is one of the most commonly diagnosed types of malignancy and is the second leading cause of cancer-related death in men in developed countries. Cyclin dependent kinase 2 associate protein 1(CDK2AP1) is an epigenetic and cell cycle regulator gene which has been downregulated in several malignancies, but its involvement in PCa has not yet been investigated in a clinical setting. We assessed the prognostic value of CDK2AP1 expression in a cohort of men diagnosed with PCa (n = 275) treated non-surgically by transurethral resection of the prostate (TURP) and studied the relationship between CDK2AP1 expression to various PCa molecular subtypes (ERG, PTEN, p53 and AR) and evaluated the association with clinical outcome. Further, we used bioinformatic tools to analyze the available TCGA PRAD transcriptomic data to explore the underlying mechanism. Our data confirmed increased expression of CDK2AP1 with higher Gleason Grade Group (GG) and metastatic PCa (p <0.0001). High CDK2AP1 expression was associated with worse overall survival (OS) (HR: 1.62, CI: 1.19−2.21, p = 0.002) and cause-specific survival (CSS) (HR: 2.012, CI 1.29−3.13, p = 0.002) using univariate analysis. When compared to each sub-molecular type. High CDK2AP1/PTEN-loss, abnormal AR or p53 expression showed even worse association to poorer OS and CCS and remained significant when adjusted for GG. Our data indicates that CDK2AP1 directly binds to p53 using the Co-Immunoprecipitation (Co-IP) technique, which was validated using molecular docking tools. This suggests that these two proteins have a significant association through several binding features and correlates with our observed clinical data. In conclusion, our results indicated that the CDK2AP1 overexpression is associate with worse OS and CSS when combined with certain PCa molecular subtypes; interaction between p53 stands out as the most prominent candidate which directly interacts with CDK2AP1.

The Expression of Proto-Oncogene ETS-Related Gene (ERG) Plays a Central Role in the Oncogenic Mechanism Involved in the Development and Progression of Prostate Cancer.

The ETS-related gene (ERG) is proto-oncogene that is classified as a member of the ETS transcription factor family, which has been found to be consistently overexpressed in about half of the patients with clinically significant prostate cancer (PCa). The overexpression of ERG can mostly be attributed to the fusion of the ERG and transmembrane serine protease 2 (TMPRSS2) genes, and this fusion is estimated to represent about 85% of all gene fusions observed in prostate cancer. Clinically, individuals with ERG gene fusion are mostly documented to have advanced tumor stages, increased mortality, and higher rates of metastasis in non-surgical cohorts. In the current review, we elucidate ERG's molecular interaction with downstream genes and the pathways associated with PCa. Studies have documented that ERG plays a central role in PCa progression due to its ability to enhance tumor growth by promoting inflammatory and angiogenic responses. ERG has also been implicated in the epithelial-mesenchymal transition (EMT) in PCa cells, which increases the ability of cancer cells to metastasize. In vivo, research has demonstrated that higher levels of ERG expression are involved with nuclear pleomorphism that prompts hyperplasia and the loss of cell polarity.

Late Diagnosis of Hirschsprung's Disease: Definition and Implication on Core Outcomes.

INTRODUCTION: Late diagnosis of Hirschsprung's disease (LDHD) may carry a poor prognosis. Its definition remains unclear and its implication on HD-related core outcomes has not been fully reported. METHODS: A single-center 20-year series was reviewed to include HD with follow-up of 1 year or more post pull-through (PT) and aged 5 years or older. We investigated six core outcomes derived from NETS1HD study by comparing the groups dichotomized by four time points using age at diagnosis (44-week gestation, 6 months, 1 year, and 3 years). Following establishment of definition of LDHD, the outcomes and complications were compared with timely diagnosis of HD (TDHD). RESULTS: Forty-nine out of eighty-six HD were included. The definition of LDHD was found to be HD diagnosed at 1 year of age or later because 3/6 core outcomes were significantly worse than TDHD. Nine patients (18%) had LDHD-median age at diagnosis 42 months (12-89) and PT performed at 57 months (12-103), mostly Soave (73%); a covering stoma was performed in 7/9, significantly higher than TDHD in 10/40 (p = 0.001). LDHD was associated with increased unplanned surgery (78% vs. 30%, p = 0.019), fecal incontinence (100% vs. 62%, p = 0.01), and permanent stoma (33% vs. 5%, p = 0.037). Major complications (56% vs. 20%, p = 0.043) and redo PT (33% vs. 5%, p = 0.037) were also higher in LDHD. CONCLUSION: LDHD could be defined as HD diagnosis at or over 1 year of age. LDHD was associated with more preoperative stoma, major postoperative complications, unplanned reoperation, and worse HD-related core outcomes.

A Survey and Critical Evaluation of Isolation, Culture, and Cryopreservation Methods of Human Amniotic Epithelial Cells.

Human amniotic epithelial cells (hAECs), derived from an epithelial cell layer of the human amniotic membrane, possess embryonic stem-like properties and are known to maintain multilineage differentiation potential. Unfortunately, an inability to expand hAECs without significantly compromising their stem cell potency has precluded their widespread use for regenerative therapies. This article critically evaluates the methods used for isolation, expansion, and cryopreservation of hAECs. We assessed the impact of these methods on ex-vivo expansion and stem cell phenotype of hAECs. Moreover, the progress and challenges to optimize clinically suitable culture conditions for an efficient ex-vivo expansion and storage of these cells are highlighted. Additionally, we also reviewed the currently used hAECs isolation and characterization methods employed in clinical trials. Despite the developments made in the last decade, significant challenges still exist to overcome limitations of ex-vivo expansion and retention of stemness of hAECs in both xenogeneic and xenofree culture conditions. Therefore, optimization and standardization of culture conditions for robust ex-vivo maintenance of hAECs without affecting tissue regenerative properties is an absolute requirement for their successful therapeutic manipulation. This review may help the researchers to optimize the methods that support ex-vivo survival, proliferation, and self-renewal properties of the hAECs.Abbreviations: AM: Human amniotic membrane; CM-HBSS: Ca++ and Mg++ free HBSS; DMEM: Dulbecco's Modified Eagle Medium; DMEM-HG: DMEM-high glucose; EMEM: Eagle's Modified Essential Medium; EMT: Epithelial-to-mesenchymal transition; EpM: Epi-life complete media; ESC: Embryonic stem cells; ESCM: Epithelial cell surface markers; hAECs: Human amniotic epithelial cells; HLA: Human leukocyte antigen; IM: Immunogenicity markers; iPSC: Induced pluripotent stem cells; KOSR; KSR: Knockout serum replacement; KSI: Key success indicators; CHM: Cell heterogeneity markers; Nanog: NANOG homeobox; Oct-4: Octamer binding transcription factor 4; OR: Operation room; P: Passage; PM: Pluripotency markers; SCM: Stem cell markers for non-differentiated cells; Sox-2: Sry-related HMG box gene 2; SSEA-4: Stage-specific embryonic antigen; TRA: Tumor rejection antigen; UC: Ultra-culture; XF: Xenogeneic free.

Regulation of Chemosensitivity in Human Medulloblastoma Cells by p53 and the PI3 Kinase Signaling Pathway.

In medulloblastoma, p53 expression has been associated with chemoresistance and radiation resistance and with poor long-term outcomes in the p53-mutated sonic hedgehog, MYC-p53, and p53-positive medulloblastoma subgroups. We previously established a direct role for p53 in supporting drug resistance in medulloblastoma cells with high basal protein expression levels (D556 and DAOY). We now show that p53 genetic suppression in medulloblastoma cells with low basal p53 protein expression levels (D283 and UW228) significantly reduced drug responsiveness, suggesting opposing roles for low p53 protein expression levels. Mechanistically, the enhanced cell death by p53 knockdown in high-p53 cells was associated with an induction of mTOR/PI3K signaling. Both mTOR inhibition and p110α/PIK3CA induction confirmed these findings, which abrogated or accentuated the enhanced chemosensitivity response in D556 cells respectively while converse was seen in D283 cells. Co-treatment with G-actin-sequestering peptide, thymosin ß4 (Tß4), induced p-AKTS473 in both p53-high and p53-low cells, enhancing chemosensitivity in D556 cells while enhancing chemoresistance in D283 and UW228 cells. IMPLICATIONS: Collectively, we identified an unexpected role for the PI3K signaling in enhancing cell death in medulloblastoma cells with high basal p53 expression. These studies indicate that levels of p53 immunopositivity may serve as a diagnostic marker of chemotherapy resistance and for defining therapeutic targeting.

A Critical Analysis of Rectal Biopsy to Exclude Hirschsprung's Disease.

INTRODUCTION: Most Hirschsprung's disease (HD) are diagnosed in young children with increased risk ("red flag"). Older children (>6 months) require open rectal biopsy (ORB) with its own impact on risk and resources. We investigated if "red flag", age, and sex used in combination could exclude HD. MATERIALS AND METHODS: "Red flags" are risk factors associated with HD, including neonatal bowel obstruction, genetic association, failure of passage of meconium in <48 hours, infantile constipation, distension with vomiting, or family history. All rectal biopsies (2015-2018) were reviewed for indications, methods, and histopathological findings. Logistic regression analysis was adopted to assess predictive value of "red flag," age, and sex (p < 0.05* was significant). RESULTS: A total of 187 children underwent 84 suction rectal biopsies and 113 ORBs (n = 197 in total). Final histopathological diagnoses were non-HD (n = 154) and HD (n = 43). Total 78% of rectal biopsies were non-HD, of which 63% by ORB. Non-HD was associated with absence of "red flag" (49 vs. 16%*), increased age at biopsy (22 months vs. 28 days*), >6 months old (62 vs. 30%*), and female gender (54 vs. 16%*), compared with HD. In the absence of "red flag," 7/82 (9%) had HD (negative predictive value = 91%). Logistic regression analysis found absent "red flag" predicted non-HD biopsy with odds ratio 4.77 (1.38, 16.47), corrected for age and sex. CONCLUSION: Negative rectal biopsy rate for HD is very high. The majority required ORB. Although "red flag" and gender, but not age, have strong predictive values, it is inadequate for excluding HD. This study supports the need for alternative strategies in excluding HD.

Tumor location and concurrent liver resection, impact survival in T2 gallbladder cancer: a meta-analysis of the literature.

Aim of doing this review was to give a uniform consensus on prognostic impact of tumor location (hepatic vs peritoneal), liver resection and adjuvant chemotherapy in gall bladder cancer and, to compare them with previous well-studied factors of survival. We systematically review PubMed, Scopus and Cochrane for relevant articles with no date restrictions, language was restricted to English. Those articles were included that had provided Hazard ratio (HR) of survival for T2 gall bladder cancer. We identified nine retrospective studies published between 2014 and 2020 with 2345 patients. Meta-analysis showed that T2b (hepatic) cancers had higher odds of mortality (HR 3.16 [2.11, 4.74], I2 = 0%). Liver resection was associated with significantly higher odds of 5-year overall survival only in T2b (2.20 [1.33, 3.63], I2 = 67%), adjuvant chemotherapy was not associated with any significant decrease in mortality risk (0.98 [0.83-1.16]. I2 = 20%). Hepatic sided gall bladder tumors carry higher odds for mortality and recurrence. T2a tumors can be managed without hepatic resection. To risk stratify patients we also formulated a scoring system for mortality risk.